Synthesis of new polycyclic γ- and δ-lactones upon activation of, and nucleophilic additions to, diazines: Influence of the activating agents

Article abstract of DOI:10.1002/ejoc.200800338

The reaction of bis(trimethylsilyl)ketene acetals 2 with N-heterocycles containing either one or two nitrogen atoms in the presence of triflic anhydride has been examined and the structures of the resulting products compared with those obtained by using m

Full text of DOI:10.1002/ejoc.200800338

FULL PAPER
DOI: 10.1002/ejoc.200800338
Synthesis of New Polycyclic γ- and δ-Lactones upon Activation of, and
Nucleophilic Additions to, Diazines: Influence of the Activating Agents
A. Garduno-Alva,[a] Y. Xu,[b][‡] N. Gualo-Soberanes,[a] J. Lopez-Cortes,[a] H. Rudler,*[b]
A. Parlier,[b] M. C. Ortega-Alfaro,[c] C. Alvarez-Toledano,[a] and R. A. Toscano[a]
Keywords: Lactones / Azo compounds / Cyclization / Silyl enol ethers / Polycycles
The reaction of bis(trimethylsilyl)ketene acetals 2 with N-
heterocycles containing either one or two nitrogen atoms in
the presence of triflic anhydride has been examined and the
structures of the resulting products compared with those ob-
tained by using methyl chloroformate as the activating agent.
Whereas pyridine, pyrazine, quinoxaline and pyrimidine led
to the same type of fused δ- or γ-lactones 4, 6, 8, 10 and 11
as with methyl chloroformate, the behaviour of pyridazine
appeared to be peculiar. In the presence of methyl chloro-
formate, this heterocycle led to δ-lactones 16 via stable dihy-
dropyridazines, with triflic anhydride, the direct formation of
γ-lactones 20 was observed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
The use of ketene acetals as potential 1,3-dinucleophiles
has emerged as a very powerful method for the synthesis of
lactones from both simple aromatic compounds as well as
from aza-aromatics.[1] Whereas in the first case the acti-
vation of the aromatic substrates was the result of the coor-
dination of their double bonds to a transition metal, in the
second case the activation of the aza-aromatics occurred
through the nitrogen atoms via the formation of pyridinium
salts. These transformations were first carried out on pyr-
idine and its derivatives: it is a two-step process giving iso-
lable intermediate monoaddition products, carboxylic acid
substituted dihydropyridines.[2] These could be oxidized in
a non-biomimetic way to afford tetrahydropyridine-fused δ-
lactones.[1b,3] Among the oxidizing agents X+, the more ef-
ficient are derived from HCl, I2, Br2 and ArCO3H
(Scheme 1).
Scheme 1.
implications are concerned are diazine derivatives, which
could be obtained by similar means: pyrazine and quinox-
aline were even more straightforward as the presence of two
nitrogen atoms, which might both be activated towards nu-
cleophilic addition upon interaction with alkyl chloro-
formates, allowed for the direct formation of γ-lactones
upon successive, formal additions of the two termini of the
dinucleophiles to the two carbon–nitrogen double bonds of
these substrates[1b,5] (Scheme 2).
Both the monoaddition products, the various dihydro-
pyridines, and the diaddition products, the fused lactones,
might be considered potentially important from a biological
point of view.[4] No less important as far as their biological
[a] Instituto de Quimica, Universidad Nacional Autonoma de
México (UNAM),
Scheme 2.
Circuito Exterior s/n, Ciudad Universitaria, 04510 México D.F.,
México
[b] Laboratoire de Chimie Organique, UMR CNRS 7611, Uni-
versité P. M. Curie,
The purpose of this paper is to show that the double
nucleophilic addition reaction of ketene acetals, which leads
to lactones, can be extended to other diazines such as pyr-
imidine and pyridazine, but that the course of the reaction
may be dependent on the nature of the nitrogen-activating
agent. Therefore, we shall first make a comparison between
the behaviour of two types of activating agents, alkyl chlo-
roformates and triflic anhydride [(CF3SO2)2O], in the reac-
Case 47, 4 place Jussieu, 75252 Paris Cedex 5, France
Fax: +33-1-44273787
E-mail: henri.rudler@upmc.fr
[c] Facultad de Quimica, Universidad Nacional Autonoma de
México (UNAM),
Circuito Exterior s/n, Ciudad Universitaria, 04510 México D.F.,
México
[‡] Present address: Aster Print Pigments,
Shanghai, China
3714
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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New Polycyclic γ- and δ-Lactones
tions with pyridine and pyrazines, and then describe the
special behaviour of pyridazine in these dinucleophilic ad-
dition reactions.
Results and Discussion
According to the literature, pyridines functionalized at
C-4 are best obtained upon their activation with either alkyl
chloroformates or triflic anhydride followed by the addition
of various C-nucleophiles.[6–12] Each method has its advan-
tages and disadvantages: triflic anhydride is expensive but
gives high yields of stable pyridinium salts and then high
yields of addition products. In the case of methyl chloro-
formate, which is cheap, the pyridinium salts are unstable
and must be used as soon as they are formed. Also, the
yields of the addition products are somewhat lower. There
is a further difference that is significant: 1-methoxycar-
bonyl-1,4-dihydropyridines, in contrast to the correspond-
ing triflates, exist as two rotamers, a fact that can compli-
cate their analyses by NMR spectroscopy. In order to deter-
mine the effect, if any, of the activating agent on the course
of these reactions, we carried out a series of experiments
with both methyl chloroformate and triflic anhydride.
Scheme 3.
gen-bonded polymers,[1b] the acid of one molecule being hy-
drogen-bonded to the oxygen of the methoxycarbonyl of
another molecule.
Reaction of Pyridine, Pyrazine and Quinoxaline with
Bis(trimethylsilyl)ketene Acetals in the Presence of Triflic
Anhydride: Formation of the Expected δ- and γ-Lactones
Triflic anhydride is known to activate pyridine towards
nucleophilic addition reactions: it has been used by one of
us in alkylamine-induced pyridine ring-opening reac-
tions,[13,14] and by Katritzky et al. in the preparation of 4-
(2-oxoalkyl)pyridines from pyridine and ketones.[15]
Figure 1. X-ray structure of compound 3b.
In this work we observed that the use of ketene acetals
in conjunction with triflic anhydride led, in the case of pyr-
idine, to results similar to those obtained with methyl chlo-
roformate as the activating agent. Thus, the one-pot reac-
tion of pyridine first with 1 equiv. of triflic anhydride at
–30 °C and then, at the same temperature, with 1.5 equiv.
of the ketene acetal 2a led, after 10 hours at room tempera-
ture, to 3a (yield 75%, m.p. 108 °C), the expected dihy-
dropyridine (Scheme 3). The NMR spectra of this com-
pound were in all respects comparable to those of the
methoxycarbonyl-protected dihydropyridines shown in
Scheme 1, all of the protons of the dihydropyridine ring ap-
pearing, however, as isolated multiplets due to the absence
of rotamers. Compound 2b behaved similarly leading to 3b
in 96% yield (white solid, m.p. 134 °C).
Surprisingly however, the intramolecular lactonization
reaction in the presence of acids did not occur: neither ex-
tended contact with silica gel nor reaction with HCl led
to the expected lactones.[1b] Nevertheless, under the same
conditions employed for the dihydropyridines bearing a
methoxycarbonyl group, 3b reacted with iodine to give a
single crystalline compound (yield 96%, m.p. 132 °C), the
physical data of which agreed in all respects with structure
4b, the corresponding iodo-lactone showing typical signals
for CO at δ = 171.7 ppm and for C–I at δ = 27.1 ppm
(Scheme 4).
Crystals suitable for X-ray structure determination were
grown from dichloromethane/hexane solutions.[16] The mo-
lecular structure is shown in Figure 1 and confirms the sug-
gested structure, the planar geometry around the nitrogen
atom and a general bent geometry of the dihydropyridine
ring similar to that previously reported.[13,15] Interestingly,
these acids appear as classical dimers formed via the car-
boxy groups. This is in contrast to acids bearing the meth-
oxycarbonyl group, which appear in the unit cell as hydro- Scheme 4.
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A final assessment was made by performing an X-ray
structure determination, which showed indeed (Figure 2)
the presence of iodine, as expected, trans with respect to the
lactone bridge.[16] Compound 3a reacted similarly and led
to 4a (yield 74%, m.p. 111 °C).
Figure 2. X-ray structure of compound 4b.
Figure 3. X-ray structure of compound 8.
The reactions of pyrazine (5) and quinoxaline (7) with
ketene acetals in the presence of methyl chloroformate have
already been outlined: they led in both cases to γ-lactones
upon successive activation of the two nitrogen atoms
(Scheme 5).[5] The reaction of pyrazine (5) and quinoxaline
(7) with 1 equiv. of the ketene acetal 2a in the presence of
2 equiv. of triflic anhydride followed the same course: the
formation in each case of a single compound, a γ-lactone,
upon double nucleophilic addition of the ketene acetal.
Thus, 5 led to 6a, and with 2b to 6b, in 47 and 50% yields,
respectively, isolated as white solids.
Reaction of Bis(trimethylsilyl)ketene Acetals with
Pyrimidine
The importance of pyrimidine (9) in biochemistry as part
of the skeleton of nucleic acids and as its oxygenated deriva-
tives is clear.[17] Much work has already been carried out
to achieve nucleophilic addition reactions on this substrate.
Especially rewarding as far as the present work is concerned
are the double nucleophilic addition reactions described by
Akiba and co-workers on activated pyrimidinium nuclei in-
volving carbon nucleophiles, which gave 2,4-disubstituted
tetrahydropyrimidines.[18] No monoadducts, such as dihy-
dropyrimidines, were observed upon activation with acetyl
chloride. It was therefore likely that pyrimidine would react
in the same way with 1 equiv. of a ketene acetal to give
directly a diaddition product, once again a δ-lactone. And
that was the case: activation with both methyl chloro-
formate or triflic anhydride led to the expected products.
Thus, the reaction of pyrimidine (9) with 1 equiv of ketene
acetal 2a and 3 equiv. of methyl chloroformate led to a
single compound (yield 42%, oil), the NMR spectroscopic
data of which agreed with a structure such as 10a, a 2,4-
diaddition product. It is a δ-lactone with a signal at δ =
173.85 ppm. The COSY NMR spectrum confirmed the
Scheme 5.
Their physical data were in all respects comparable to presence of a highly deshielded signal, a singlet at δ =
those of the previously reported compounds. Similarly, 7.65 ppm, which was attributed to the isolated proton 1-
quinoxaline (7) led upon reaction with 2a to the lactone 8 H. An HMQC correlation indicated that the signal at δ =
(yield 41%, m.p. 187 °C) (Scheme 5). The structures of 53.56 ppm in the 13C NMR spectrum was attributable to
these γ-lactones were assessed by an X-ray analysis carried C-5. This carbon bears a proton that is correlated with 6-
out on 8 (Figure 3), which confirmed the addition of the H (at δH = 5.31 ppm; δC = 104.99 ppm), a proton of the
1,3-dinucleophile to the carbon–nitrogen double bonds of double bond. Under similar conditions, pyrimidine (9) re-
the starting compounds.[16]
acted with 2b to give 10b as an oil in 90% yield (Scheme 6).
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New Polycyclic γ- and δ-Lactones
monoaddition product.[18] We observed similar behaviour
for the reaction of 12 and 13 in the presence of methyl chlo-
roformate, leading to 14a (Scheme 7).
Scheme 7.
Scheme 6.
It was therefore evident that a bis(trimethylsilyl)ketene
acetal 2a would behave similarly. And that was indeed the
case. Even with 2 equiv. of methyl chloroformate and
2 equiv. of bis(trimethylsilyl)ketene acetal 2a, pyridazine
(12) led, upon purification by silica gel column chromatog-
raphy, to a single monoaddition product, the acid 15a
(Scheme 8), isolated as a solid (yield 62%, m.p. 124 °C).
The NMR spectroscopic data of this acid were only slightly
different to those of the corresponding ester 14a (see the
Exp. Sect.).
Activation with triflic anhydride led to similar products:
thus, pyrimidine (9) with a two-fold excess of triflic anhy-
dride and ketene acetals 2a,b led to 11a (yield 42%, m.p.
78 °C) and 11b (yield 55%, m.p. 88 °C), respectively. The
spectroscopic data were again in agreement with the ex-
pected structures. Confirmation of the structure of these
double addition products came from an X-ray analysis (Fig-
ure 4) carried out on crystals of 11a, which again indicated
a planar geometry around the two nitrogen atoms.[16]
Scheme 8.
Confirmation of the suggested structure came from an
X-ray analysis carried out on a single crystal of 15a.[16] Fig-
ure 5 indicates indeed that the addition took place at C-4,
and that the six atoms of the cycle lie almost in the same
plane. This structure, and especially the arrangement of the
molecules in the lattice, warrants a special comment. In-
deed, compound 15a crystallized in the orthorhombic sys-
tem with space group Pca21 and with two independent
molecules of opposite stereochemistry in the asymmetric
unit. In both molecules the 1,4-dihydropyridazine ring is in
an almost planar boat conformation (mean plane devia-
tions, for molecule A: 0.067 Å; for molecule B: 0.0815 Å).
Moreover, the two independent components in 15a are
linked, forming homochiral endless chains along the a axis
by a combination of simultaneous O–H···N hydrogen bonds
and O–H···O interactions. These chains assemble in an anti-
parallel mode, forming a unique double-stranded helix (Fig-
ure 6) by virtue of π-stacking interactions (Figure 5) be-
tween the methyl 1,4-dihydropyridazine-1-carboxylate moi-
eties.
Figure 4. X-ray structure of compound 11a.
Reaction of Pyridazine with Ketene Acetals Ϫ The
Activation Agent Makes the Difference: Formation of δ-
Versus γ-Lactones
Methyl Chloroformate Activation: Formation of a δ-
Lactone upon Iodocyclization via an Isolable
Dihydropyridazine
The reaction of pyridazine (12) with mono(trimethyl-
When dihydropyridazine 15a was treated with iodine in
silyl)ketene acetals of the type 13 in the presence of ethyl the presence of an aqueous saturated solution of sodium
chloroformate has previously been studied by Akiba and hydrogen carbonate for 3 days, the formation of a new
co-workers; they observed the formation of only a C-4 product was observed. After removal of excess iodine, the
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H. Rudler et al.
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Scheme 9.
azines 15a,b behaved like 1,4-dihydropyridines, the lactoni-
zation reaction taking place upon interaction of the carb-
oxy group with the polarized γ,δ-carbon–carbon double
bonds of these substrates.
Figure 5. X-ray structure of compound 15a.
Figure 7. X-ray structure of compound 16a.
Triflic Anhydride Activation of Pyridazine: Direct
Formation of γ-Lactones
The reactivity was absolutely different when 2 equiv. of
triflic anhydride were added at –30 °C to a dichloromethane
solution of pyridazine (12) and after 10 min at the same
temperature 2 equiv. of bis(trimethylsilyl)ketene acetal 2a
were also added. After slow heating to room temperature
and stirring for 12 h, a new product was isolated upon silica
gel chromatography (yield 20%, m.p. 94 °C). The 13C NMR
spectrum first confirmed the introduction of the SO2CF3
group and seemed also in agreement with the presence of a
γ-lactone, with a signal at δ = 179.91 ppm in the 13C NMR
Figure 6. Helix structure of 15a in the crystal lattice.
organic residue was subjected to silica gel column spectrum arising from the CO group as well as a band at
chromatography. A single crystalline compound 16a was 1786 cm–1 in the IR spectrum. In the same spectra, the pres-
isolated (yield 79%, m.p. 116 °C, decomposition). The ence of another carbonyl function was also observed (at
NMR spectroscopic data agreed with the presence of two 176.89 ppm and 1720 cm–1, respectively). Surprisingly, be-
carbonyl groups: δ = 172.4 ppm for the δ-lactone and δ = sides signals for four different protons, signals for four
1
154.0 ppm for the methoxycarbonyl group. Moreover, the methyl groups were also apparent in the H NMR spec-
presence of a secondary iodine was confirmed by signals at trum, two of them as singlets at δ = 1.27 and 1.44 ppm, two
δ = 4.91 and 27.5 ppm, respectively, in the 1H and 13C of them as doublets at δ = 1.08 and 1.22 ppm (J = 7.0 Hz).
NMR spectra (Scheme 9).
This was in agreement with the introduction of the elements
A single-crystal analysis carried out on 16a (Figure 7) of 2 equiv. of the ketene acetal. These latter signals more
confirmed these data and again, as expected, the trans rela- probably belonged, therefore, to an isopropyl group in an
tionship between the lactone bridge and the iodine.[16] It asymmetric environment, a structural feature also con-
appeared, therefore, that the intermediate dihydropyrid- firmed by the presence of a heptet at δ = 3.19 ppm, integrat-
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New Polycyclic γ- and δ-Lactones
ing for one proton. Among the signals of the isolated pro-
tons of the ring system, three of them were highly deshield-
ed: δ = 6.91 (2 H) and 5.43 (1 H) ppm. Two were attrib-
utable to those of a double bond, as in 14a or 15a, and one
to the typical deshielded N–CH–O proton of these lactones,
an observation that was also in agreement with the presence
of a signal at δ = 80.76 ppm in the 13C NMR spectrum.
Similar features appeared in the NMR spectra of the
product obtained by reaction of 12 with 2b (31% yield, m.p.
1
114 °C). Its H NMR spectrum clearly showed signals for
the two coupled hydrogen atoms of the double bond, which
appeared as two doublets at δ = 6.95 and 5.43 ppm (J =
8 Hz), and for the OCHN proton at δ = 6.87 ppm, which
appeared as a doublet (J = 6 Hz). Taken together with the
mass spectra, and with the structure of 14a or 15a obtained
upon activation with methyl chloroformate, these data
seemed to support structures 20a,b, which arise from nucleo-
philic attack of the carbon and oxygen termini of the dinu-
cleophile at C-4 and C-3 of pyridazine, respectively
(Scheme 10).
Figure 8. X-ray structure of compound 20a.
observed amide 20.[19] Such an evolution of intermediate 18
cannot take place when the activation is promoted by
methyl chloroformate (Scheme 11).
Scheme 10.
The structures of the two products were assessed by X-
ray analysis.[16] As shown for 20a in Figure 8, a γ-lactone
cis-fused to a tetrahydropyridazine had indeed formed, one
nitrogen bearing a trifluoromethanesulfonyl group, as ex-
pected from the NMR spectroscopic data, the other one,
surprisingly, an acyl group, originating most probably from
the starting ketene acetal. Both nitrogen atoms adopt a
planar geometry due to electron delocalization either on the
oxygen atoms of the triflyl or on the oxygen of the amide.
Thus, in contrast to what was observed with methyl chloro-
formate, a surprising, novel, direct activation of the two ni-
trogen atoms takes place, which allows the double nucleo-
philic addition to occur.
Scheme 11.
Conclusions
As a general rule, the reaction of pyridines, pyrazines,
quinoxalines and pyrimidines with ketene acetals of the
type 2 led to a series of δ- and γ-lactones whatever the nitro-
A mechanism for the formation of 20a,b can be sug- gen activating agent. Note, in the case of pyridine, no spon-
gested. Although nucleophilic addition to the intermediate taneous or acid-mediated lactonization of the intermediate
imine 18 seemed possible, the nature and origin of the elec- trifluoromethanesulfonyl-substituted dihydropyridines was
trophile on the nitrogen atom were not clear in the absence observed. In the case of pyridazine, strikingly different be-
of any ester derivatives of the acid employed as the starting haviour was observed. An intermediate dihydropyridazine
material.[1] It is therefore likely that the intermediate dihy- was isolated upon activation with methyl chloroformate.
dropyridazine 18, formed upon reaction of the ketene ace- This intermediate then reacted with iodine, similarly to the
tals with the starting iminium triflate 17, underwent a Me3- dihydropyridines 3, to give a δ-lactone. No such intermedi-
SiOTf-mediated cyclization, leading in the presence of ex- ate was observed in the case of triflic anhydride; the interac-
cess ketene acetals 2 to the adduct 19, and, after hydrolysis tion of the second nitrogen atom with an activated ketene
of the α-TMS amide, loss of the TMS group to give the acetal promoted
a
direct, intramolecular reaction
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H. Rudler et al.
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181.7 (COOH), 119.5 (J = 324.79 Hz, CF3), 120.9 (C-2), 108.5 (C-
3), 50.2 (C-2Ј), 38.6 (C-4), 33.6, 33.4, 25.1, 20.7, 20.3 (CH2) ppm.
MS (EI): m/z = 338 [M – 1]+.
of the oxygen terminus of the ketene acetal with the electro-
philic carbon of an imine, leading to a γ-lactone. Finally,
almost all of the new products described herein have been
characterized by X-ray crystallography.
Experimental Section
General Information: Reactions were run under inert argon. All
glassware was dried in an oven prior to use. Anhydrous solvents
were obtained by distillation under an inert atmosphere over so-
dium benzophenone for THF, and P2O5 for dichloromethane. Col-
umn chromatography was performed using 70–230 mesh silica gel.
Melting points were obtained with a Kofler hot-plate and are un-
corrected. Nuclear magnetic resonance spectra were recorded with
a Bruker AV 400 or JEOL Eclipse +300 spectrometer. Chemical
General Procedure for the Synthesis of Lactones 4a and 4b: A
dichloromethane solution (5 mL) of iodine was added through a
cannula followed by a saturated solution of NaHCO3 (10 mL) to a
solution of N-(trifluoromethylsulfonyl)-1,4-dihydro-4-pyridinyl-
ethanoic acid (3) in dry dichloromethane (40 mL) under an inert
atmosphere. The mixture was stirred at room temperature for 4 d.
Then a 10% solution of Na2SO3 was added (40 mL), the mixture
was transferred to a separating funnel and decanted. The aqueous
phase was extracted four times with dichloromethane. The organic
phase was dried with Na2SO4. After evaporation of the solvent
under reduced pressure, the crude residue was purified by column
chromatography. Elution with ethyl acetate/petroleum ether gave 4.
1
shifts for the H NMR spectra were recorded in parts per million
from tetramethylsilane with the solvent resonance as the internal
standard (chloroform, δ = 7.25 ppm). Data are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, m = multiplet and br = broad), coupling constant (J) in
Hz and integration. Chemical shifts for the 13C NMR spectra were
recorded in parts per million from tetramethylsilane using the cen-
tral peak of CDCl3 (δ = 77.1 ppm) as the internal standard. IR
spectra were recorded with a Nicolet FT-1 Magna 750 spectrometer
using KBr pellets. Mass spectra were recorded with a JEOL JMS-
AX 505 HA spectrometer at 70 eV using the electronic impact (EI)
technique. The ketene acetals 2a and 2b were prepared according
to published methods.[20]
Compound 4a (C10H11F3INO4S, M = 425 g/mol) was prepared
starting from 3a (0.508 g, 1.69 mmol) and iodine (0.457 g,
1.8 mmol) and was obtained as a yellow solid, m.p. 111 °C
(0.5386 g, 1.26 mmol, 74%). IR: ν = 1762 (C=O) cm–1 1H NMR
.
˜
(300 MHz, CDCl3): δ = 6.56 (d, J = 8 Hz, 7-H), 6.07 (br. s, 1 H,
1-H), 5.38 (m, 1 H, 6-H), 5.09 (ddd, J = 1.95, 1.9, 1.7 Hz, 1 H, 9-
H), 2.51 (dd, J = 4.4, 1.9 Hz, 1 H, 5-H), 1.47 (s, 3 H, CH3), 1.41
(s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.7 (C=O),
119 (q, J = 300 Hz, CF3), 120.5 (C-7), 109 (C-6), 84.6 (C-1), 46.3
(C-4), 44.0 (C-5), 27.1 (C-9), 26.0 (CH3) ppm. MS (EI): m/z (%) =
425 (60) [M]+, 338 (100) [M – 87]+, 212 (40) [M – 213]+.
General Procedure for the Synthesis of Compounds 3a and 3b: Tri-
fluoromethanesulfonic anhydride was added by syringe to a solu-
tion of pyridine in dry dichloromethane (20 mL) cooled to –30 °C
and under an inert atmosphere. The formation of a white precipi-
tate was observed. After 10 min, the corresponding bis(trimethylsi-
lyl)ketene acetal was added. After 5 min, the mixture was warmed
to room temperature and stirred for 17 h. Water was added
(30 mL), the mixture was transferred to a separating funnel and
decanted. The aqueous phase was extracted four times with dichlo-
romethane. Base extraction followed by reacidification and extrac-
tion with dichloromethane (Na2CO3 then HCl) allowed the acid to
be isolated as a white solid after evaporation of the solvent under
reduced pressure.
Compound 4b (C13H15F3INO4S, M = 465 g/mol) was prepared
starting from 3b (0.5 g, 1.47 mmol) and iodine (0.37 g, 1.47 mmol)
and was obtained as a yellow solid, m.p. 132 °C (0.6626 g,
1
1.42 mmol, 96%). IR: ν = 1753 (C=O) cm–1. H NMR (300 MHz,
˜
CDCl3): δ = 6.57 (d, J = 8.4 Hz, 1 H, 7-H), 6.04 (m, 1 H, 1-H),
5.37 (dt, J = 2.6, 1.9 Hz, 1 H, 6-H), 5.05 (d, J = 1.8 Hz, 1 H, 9-
H), 2.90 (d, J = 6.3 Hz, 1 H, 5-H), 1.46–2.07 (m, 10 H, CH2) ppm.
13C NMR (75 MHz, CDCl3): δ = 171.7 (C=O), 119.4 (J
=
Compound 3a (C10H12F3NO4S, M = 299 g/mol) was prepared
starting from pyridine (0.5 mL, 0.511 g, 6.47 mmol), trifluorometh-
anesulfonic anhydride (1 mL, 1.8258 g, 6.47 mmol) and acetal 2a
(2.25 mL, 2.25 g, 9.705 mmol) and was obtained as a white solid,
319.3 Hz, CF3), 120.8 (C-7), 108.3 (C-6), 83.8 (C-1), 50.1 (C-4),
38.5 (C-5), 33.5 (CH2), 33.1 (CH2), 32.4 (C-9), 25.1 (CH2), 21.3
(CH2), 20.7 (CH2) ppm. MS (EI): m/z = 464 [M – 1]+.
m.p. 108 °C (1.46 g, 4.87 mmol, 75%). IR: ν = 1706 (C=O) cm–1
.
˜
1H NMR (300 MHz, CDCl3): δ = 11.30 (s, 1 H, COOH), 6.55 (d,
J = 7.7 Hz, 2 H, 2-H and 6-H), 5.09 (d, J = 3.03 Hz, 2 H, 3-H and
5-H), 3.39 (s, 1 H, 4-H), 1.18 (s, 6 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 183.4 (COOH), 119.6 (J = 324.79 Hz, CF3),
123.8 (C-2), 109.6 (C-2Ј), 46.8 (C-5), 39.4 (C-4), 21.3 (CH3) ppm.
MS (EI): m/z (%) = 298 (20) [M – 1]+, 212 (100) [M – 87]+.
Compound 3b (C13H16F3NO4S, M = 339 g/mol) was prepared
starting from pyridine (2 mL, 2.044 g, 25.88 mmol), trifluorometh-
anesulfonic anhydride (4.34 mL, 7.29 g, 25.88 mmol) and acetal 2b
(7 mL, 7.0312 g, 25.88 mmol) and was obtained as a white solid,
Synthesis of Lactones 6a and 6b from Pyrazine (5), and Lactone 8
from Quinoxaline (7): The same procedure as described for the syn-
thesis of 3a and 3b was used. The crude was purified by column
chromatography. Elution with ethyl acetate/petroleum ether gave 6
or 8.
m.p. 134 °C (8.46 g, 24.93 mmol, 96%). IR: ν = 1688 (C=O) cm–1
.
˜
1H NMR (300 MHz, CDCl3): δ = 9.27 (s, 1 H, COOH), 6.54 (d, J
= 8 Hz, 2 H, 2-H and 6-H), 5.10 (dd, J = 8, 4 Hz, 2 H, 3-H and
5-H), 3.19 (s, 1 H, 4-H), 2.04 (m, 4 H, CH2), 1.67 (m, 2 H, CH2),
1.17–1.39 (m, 4 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
Compound 6a (C10H10F6N2O6S2, M = 432 g/mol) was prepared
starting from 5 (0.290 mL, 0.300 g, 3.74 mmol), trifluoromethane-
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New Polycyclic γ- and δ-Lactones
sulfonic anhydride (1.26 mL, 2.11 g, 7.49 mmol) and acetal 2a
7.30 (s, 1 H, 1-H), 6.83 (d, J = 8 Hz, 1 H, 7-H), 5.27 (m, 1 H, 6-
H), 4.83 (m, 1 H, 5-H): 3.86 (s, 6 H, OCH3), 1.18–1.76 [m, 10 H,
(CH2)5] ppm. 13C NMR (100 MHz, CDCl3): δ = 172.40 (C=O),
(1 mL, 0.960 g, 4.11 mmol) and was obtained as a white solid, m.p.
128 °C (0.759 g, 1.76 mmol, 47%). IR: ν = 1809 (C=O) cm–1 1H
.
˜
NMR (300 MHz, CDCl3): δ = 6.39 (m, 2 H, 2-H and 3-H), 6.22 151.90 (CO2CH3), 124.90 (C-7), 105.00 (C-6), 87.20 (C-1), 54.90
(d, J = 7.56 Hz, 1 H, 4a-H), 4.83 (d, J = 7.83 Hz, 1 H, 7a-H), 1.43
(s, 3 H, CH3), 1.34 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 175.43 (C=O), 126, 121, 117, 113 (2 CF3), 116.06 (C-
2), 114.06 (C-3), 82.94 (C-4a), 66.25 (C-7a), 43.69 (C-7), 25.49
(CH3), 20.11 (CH3) ppm. MS (EI): m/z (%) = 432 (50) [M]+, 299
(100) [M – 133]+, 271 (30) [M – 161]+, 229 (30) [M – 203]+, 201
(40) [M – 231]+.
(OCH3), 53.20 (C-5), 45.48 (C-4), 30.08–23.52 [(CH2)5] ppm. MS:
calcd. for C15H21N2O6 [MH] 325; found 325.
Compound 6b (C13H14F6N2O6S2, M = 472 g/mol) was prepared
starting from 5 (0.485 mL, 0.500 g, 6.24 mmol), trifluoromethane-
sulfonic anhydride (2.1 mL, 3.52 g, 12.48 mmol) and acetal 2b
(3.4 mL, 3.4 g, 12.48 mmol) and was obtained as a white solid, m.p.
Synthesis of Lactones 11a and 11b from Pyrimidine (9): The same
procedure as described for the synthesis of 3a and 3b was used. The
crude was purified by chromatography. Elution with ethyl acetate/
petroleum ether gave 11.
111 °C (1.472 g, 3.12 mmol, 50%). IR: ν = 1792 (C=O) cm–1 1H
.
˜
NMR (300 MHz, CDCl3): δ = 6.45 (d, J = 5.34 Hz, 1 H, 2-H), 6.36
(d, J = 5.49 Hz, 1 H, 3-H), 6.16 (d, J = 7.83 Hz, 1 H, 4a-H), 4.76
(d, J = 7.83 Hz, 1 H, 7a-H), 2.1–1.5 [m, 10 H, (CH2)5] ppm. 13C
NMR (75 MHz, CDCl3): δ = 173.19 (C=O), 126, 121, 117, 113 (2
CF3), 117.57 (C-2), 113.98 (C-3), 82.86 (C-4a), 67.28 (C-7a), 45.12
(C-7), 34.49, 29.23, 24.49, 20.94, 20.49 [(CH2)5] ppm. MS (EI): m/z
(%) = 472 (40) [M]+, 339 (100) [M – 133]+, 311 (35) [M – 161]+,
283 (5) [M – 189]+, 213 (35) [M – 259]+.
Compound 11a (C10H10F6N2O6S2, M = 432 g/mol) was prepared
starting from 9 (0.3 mL, 0.304 g, 3.8 mmol), trifluoromethanesulfo-
nic anhydride (1.256 mL, 2.11 g, 7.5 mmol) and acetal 2a (1.74 mL,
1.74 g, 7.5 mmol) and was obtained as a white solid, m.p. 78 °C
(0.689 g, 1.59 mmol, 42%). IR: ν = 1774 (C=O) cm–1 1H NMR
.
˜
(300 MHz, CDCl3): δ = 7.14 (s, 1 H, 1-H), 6.67 (d, J = 8.67 Hz, 1
H, 7-H), 5.59 (m, 1 H, 6-H), 4.26 (d, J = 5.22 Hz, 1 H, 5-H), 1.49 (s,
3 H, CH3), 1.39 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 169.17 (C=O), 125.58, 121, 117, 112.83 (CF3), 121.55 (C-7),
107.07 (C-6), 87.01 (C-1), 56.31 (C-5), 44.94 (C-4), 25.75 (CH3),
22.27 (CH3) ppm. MS (EI): m/z (%) = 432 (5) [M]+, 299 (30) [M –
133]+, 213 (5) [M – 219]+, 122 (10) [M – 310]+, 70 (100) [M –
362]+.
Compound 8 (C14H12F6N2O6S2, M = 482 g/mol) was prepared
starting from 7 (0.27 mL, 0.300 g, 2.3 mmol), trifluoromethanesul-
fonic anhydride (0.775 mL, 1.3 g, 7.46 mmol) and acetal 2a
(0.59 mL, 0.590 g, 2.5 mmol) and was obtained as a white solid,
m.p. 187 °C (0.454 g, 0.943 mmol, 41%). IR: ν = 1809 (C=O) cm–1
.
˜
1H NMR (300 MHz, CDCl3): δ = 7.65–7.41 (m, 4 H, arom.), 6.66
(d, J = 7.56 Hz, 1 H, 4a-H), 5.09 (d, J = 7.68 Hz, 1 H, 7a-H), 1.42
(s, 3 H, CH3), 1.33 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 175.39 (C=O), 130.14, 129.14, 127.17, 125.15 (arom.),
122.06, 121.33, 117.76, 117.07 (CF3), 87.04 (C-4a), 70.54 (C-7a),
43.63 (C-7), 26.50 (CH3), 19.42 (CH3) ppm. MS (EI): m/z (%) =
482 (30) [M]+, 349 (20) [M – 133]+, 263 (100) [M – 219]+, 130 (20)
[M – 352]+.
Compound 11b (C13H14F6N2O6S2, M = 472) was prepared starting
from 9 (0.3 mL, 0.300 g, 3.8 mmol), trifluoromethanesulfonic anhy-
dride (1.26 mL, 2.11 g, 7.5 mmol) and acetal 2b (2 mL, 2.04 g,
7.5 mmol) and was obtained as a white solid, m.p. 88 °C (0.986 g,
1
2.09 mmol, 55%). IR: ν = 1775 (C=O) cm–1. H NMR (300 MHz,
˜
CDCl3): δ = 7.09 (s, 1 H, 1-H), 6.67 (d, J = 8.67 Hz, 1 H, 7-H),
5.56 (m, 1 H, 6-H), 4.60 (d, J = 5.22 Hz, 1 H, 5-H), 2.12–1.36 [m,
10 H, (CH2)5] ppm. 13C NMR (75 MHz, CDCl3): δ = 168.75
(C=O), 125.5, 121, 117, 113 (2 CF3), 121.67 (C-7), 106.68 (C-6),
86.33 (C-1), 52.41 (C-5), 48.42 (C-4), 32.46, 30.71, 24.75, 20.71
(CH2)5 ppm. MS (EI): m/z (%) = 472 (5) [M]+, 339 (40) [M –
133]+, 213 (5) [M – 259]+, 110 (100) [M – 362]+.
Synthesis of Lactones 10a and 10b from Pyrimidine (9): Methyl
chloroformate (0.769 mL, 0.940 g, 10 mmol) in dichloromethane
(10 mL) was slowly added at room temperature to a solution of
bis(trimethylsilyl)ketene acetal 2a or 2b (3.5 mmol) and pyrimidine
(9) (0.197 mL, 0.20 g, 2.5 mmol) in dichloromethane (40 mL). Stir-
ring for 2 h followed by evaporation of the solvent gave an oil,
which was purified by column chromatography. Elution with ethyl
acetate/petroleum ether gave 10a or 10b.
Synthesis of Ester 14a from Pyridazine (12): The same procedure
as described for the synthesis of 10a and 10b was used. Compound
14a was prepared starting from methyl chloroformate (0.769 mL,
0.940 g, 10 mmol), monosilylated ketene acetal 13 (0.710 mL,
0.609 g, 3.5 mmol) and pyridazine (12) (0.181 mL, 0.20 g,
2.5 mmol) as an oil, which was purified by column chromatog-
raphy. Elution with ethyl acetate/petroleum ether gave 14a
(C12H16N2O4, M = 240 g/mol) as an oil (0.480 g, 2.0 mmol, 80%).
1H NMR (400 MHz, CDCl3): δ = 6.88 (d, J = 8 Hz, 1 H, 6-H),
6.69 (m, 1 H, 3-H), 4.64 (m, 1 H, 5-H), 3.62 (s, 3 H, OCH3), 3.44
(s, 3 H, OCH3), 3.06 (m, 1 H, 4-H), 0.94 and 0.90 [s, 6 H, (CH3)2-
C] ppm. 13C NMR (100 MHz, CDCl3): δ = 176.00 (CCO2CH3),
Compound 10a (C12H16N2O6, M = 284 g/mol) was obtained as an
oil (0.30 g, 1.05 mmol, 42%). 1H NMR (400 MHz, CDCl3): δ =
7.65 (s, 1 H, 1-H), 6.84 (d, J = 8 Hz, 1 H, 7-H), 5.31 (m, 1 H, 6-
H), 4.42 (m, 1 H, 5-H), 3.84 (s, 6 H, OCH3), 1.35 (s, 6 H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.85 (C=O),
151.48 (CO2CH3), 122.19 (C-7), 104.99 (C-6), 85.17 (C-1), 54.29
(OCH3), 53.56 (C-5), 45.49 (C-4), 26.08 and 22.60 (CH3) ppm.
HRMS: calcd. for C12H17N2O6 [MH] 285.1087; found 285.1084.
Compound 10b (C15H20N2O6, M = 324 g/mol) was obtained as an
oil (0.730 g, 2.25 mmol, 90%). 1H NMR (400 MHz, CDCl3): δ =
Eur. J. Org. Chem. 2008, 3714–3723
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3721

H. Rudler et al.
94 °C (0.274 g, 0.741 mmol, 20%). IR: ν = 1786 (C=O lactone),
FULL PAPER
152.5 (NCO2CH3), 143.3 (C-3), 124.9 (C-6), 101.7 (C-5),
.
53.9 (OCH3), 52.10 (OCH3), 47.0 (C-2Ј), 39.80 (C-4), 21.64 1720 (NCO) cm–1 1H NMR (300 MHz, CDCl3): δ = 6.91 (d, J =
˜
[(CH3)2C] ppm.
8 Hz, 2 H, 3-H and 7a-H), 5.43 (dd, J = 8, 3 Hz 1 H, 4-H), 3.19
(m, 1 H, 2Ј-H), 2.89 (m, 1 H, 4a-H), 1.44 (s, 3 H, CH3), 1.27 (s, 3
H, CH3), 1.22 (d, J = 7 Hz, 3 H, CH3), 1.08 (d, J = 7 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 179.91 (C=O lac-
tone), 176.89 (NC=O), 125.88 (C-3), 112.59 (C-4), 80.76 (C-7a),
45.17 (C-5), 41.92 (C-4a), 30.90 (C-2Ј) 25.62 (5-CH3), 20.56 (5-
CH3), 19.77 (2Ј-CH3), 18.56 (2Ј-CH3) ppm. MS (EI): m/z (%) = 370
(5) [M]+, 237 (10) [M – 133]+, 213 (100) [M – 157]+, 167 (50) [M –
203]+.
Synthesis of Acid 15a from Pyridazine (12): The same procedure as
described above was used. Compound 15a was prepared starting
from methyl chloroformate (0.579 mL, 0.708 g, 7.5 mmol), bis(tri-
methylsilyl)ketene acetal 2a (1.74 mL, 1.74 g, 7.5 mmol) and pyrid-
azine (12) (0.3 mL, 0.304 g, 3.8 mmol) as an oil, which was purified
by chromatography. Elution with ethyl acetate/petroleum ether gave
15a (C10H14N2O4, M = 226 g/mol) as a white solid, m.p. 124 °C
(0.532 g, 2.38 mmol, 62%). 1H NMR (300 MHz, CDCl3): δ = 11.00
(s, 1 H, COOH), 7.18 (d, J = 8 Hz, 1 H, 6-H), 6.96 (m, 1 H, 3-H),
4.96 (m, 1 H, 5-H), 3.91 (s, 3 H, OCH3), 3.38 (m, 1 H, 4-H), 1.26
and 1.22 [s, 6 H, (CH3)2C] ppm. 13C NMR (75 MHz, CDCl3): δ =
181.7 (COOH), 152.6 (CO2CH3), 143.4 (C-3), 125.0 (C-6), 101.7
(C-5), 54.2 (OCH3), 46.9 (C-2Ј), 39.5 (C-4), 21.5 [(CH3)2C] ppm.
MS (EI): m/z (%) = 226 (3) [M]+, 139 (100) [M – 87]+, 95 (90) [M –
131]+.
Compound 20b (C19H125F3N2O5S, M = 450 g/mol) was prepared
starting from 12 (0.275 mL, 0.304 g, 3.8 mmol), trifluoromethane-
sulfonic anhydride (1.26 mL, 2.11 g, 7.5 mmol) and acetal 2b
(2 mL, 2.04 g, 7.5 mmol) and was obtained as a white solid, m.p.
114 °C (0.530 g, 1.178 mmol, 31%). IR: ν = 1777 (C=O lactone),
˜
1709 (NCO) cm–1 1H NMR (300 MHz, CDCl3): δ = 6.95 (d, J =
.
8 Hz, 1 H, 3-H), 6.87 (d, J = 6 Hz, 1 H, 7a-H), 5.43 (dd, J = 8,
3 Hz, 1 H, 4-H), 3.08 (m, 1 H, 2Ј-H), 2.87 (m, 1 H, 4a-H), 1.85–
1.25 (m, 20 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 178.90
(C=O lactone), 175.92 (NC=O), 126.46 (C-3), 112.15 (C-4), 80.75
(C-7a), 49.44 (C-5), 40.79 (C-4a), 38.50 (C-2Ј), 32.70, 29.89, 29.19,
28.30, 25.71, 25.54, 25.04, 24.91, 22.44, 21.96 (CH2) ppm. MS (EI):
m/z (%) = 450 (3) [M]+, 317 (5) [M – 133]+, 213 (100) [M – 237]+.
Synthesis of Lactone 16a from Acid 15a: The same procedure as
described for the synthesis of 4a and 4b was used. Compound 16a
was prepared starting from 15a (0.3 g, 1.33 mmol) and iodine
(0.68 g, 2.66 mmol). The crude residue was purified by column
chromatography. Elution with ethyl acetate/petroleum ether gave
16a (C10H13IN2O4, M = 352 g/mol) as a yellow solid, m.p. 116 °C
Acknowledgement
Universidad Nacional Autónoma de México (UNAM) is acknowl-
edged for grants (UNAM DGAPA-PAPIT-IN222808) to A. G.-A.
and N. G.-S.
1
(dec.) (0.370 g, 1.051 mmol, 79%). H NMR (300 MHz, CDCl3): δ
= 7.16 (s, 1 H, 1-H), 6.48 (s, 1 H, 4-H), 4.91 (m, 1 H, 9-H), 3.96
(s, 3 H, OCH3), 2.66 (m, 1 H, 5-H), 1.45 and 1.47 [s, 6 H, (CH3)2-
C] ppm. 13C NMR (75 MHz, CDCl3): δ = 172.4 (CO), 154.0
(CO2CH3), 142.1 (C-4), 80.91 (C-1), 54.7 (OCH3), 46.2 (C-6), 45.2
(C-5), 27.5 (C-9), 25.7 [(CH3)2C] ppm. MS (EI): m/z (%) = 352 (20)
[M]+, 265 (7) [M – 87]+, 181 (100) [M – 171]+, 137 (70) [M –
215]+.
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Synthesis of Lactones 20a and 20b from Pyridazine (12): The same
procedure as described for the synthesis of 3a and 3b was used. The
crude was purified by chromatography. Elution with ethyl acetate/
petroleum ether gave 20.
Compound 20a (C13H17F3N2O5S, M = 370 g/mol) was prepared
starting from 12 (0.275 mL, 0.304 g, 3.8 mmol), trifluoromethane-
sulfonic anhydride (1.26 mL, 2.11 g, 7.5 mmol) and acetal 2a
(1.74 mL, 1.74 g, 7.5 mmol) and was obtained as a white solid, m.p.
3722
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3714–3723

New Polycyclic γ- and δ-Lactones
[11]
[12]
[16] CCDC-678784 (for 3b), -678785 (for 4b), -678786 (for 8),
-678787 (for 11a), -678788 (for 11b), -678789 (for 15a), -678790
(for 16a), -678791 (for 16b), -678792 (for 20a) contain the sup-
plementary crystallographic data. These data can be obtained
free of charge from The Cambridge Crystallographic Data
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Received: April 2, 2008
Published Online: June 13, 2008
Eur. J. Org. Chem. 2008, 3714–3723
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3723